β-Carotene Oxygenase 2 Genotype Modulates the Impact of Dietary Lycopene on Gene Expression during Early TRAMP Prostate Carcinogenesis

Abstract

Background Epidemiologic studies suggests lycopene and tomato intake are inversely associated with human prostate cancer incidence. Genetically-driven murine prostate carcinogenesis (TRAMP model) is inhibited by lycopene- or tomato-feeding, and these effects are modulated by beta-carotene oxygenase 2 (Bco2) genotype. Objectives We seek insight into this interaction through evaluation of prostate gene expression patterns during early TRAMP carcinogenesis. Methods Three-week-old TRAMP/+ or TRAMP/– x Bco2+/+ or Bco2–/– mice were fed a control, lycopene beadlet, or 10% tomato powder-containing semi-purified diet (providing 0, 384 and 462 mg lycopene/kg diet, respectively) for 5 weeks. Gene expression patterns were evaluated by prostate cancer- and cholesterol and lipoprotein metabolism-focused arrays at 8 weeks-of-age. Results TRAMP genotype profoundly alters gene expression patterns, specifically inducing pathways associated with cell survival (z-score = 2.09, –log(P-value) = 29.2), p53 signaling (z-score 1.13, –log(P-value) = 13.5), and PI3K/AKT signaling (z-score = 0.302, –log(P-value) = 12.1), while repressing PTEN signaling (z-score = -0.905, –log(P-value) = 12.3), cholesterol synthesis (z-score = –1.941, –log(P-value) = 26.2), and LXR/RXR pathway activation (z-score = –1.941, –log(P-value) = 23.1). In comparison, lycopene- and tomato-feeding modestly modulate strong procarcinogenic TRAMP signaling. Lycopene decreased gene expression related to carcinogenesis (Nkx3-1), tomato feeding increased expression of a gene involved in circadian regulation (Arntl), and tomato and/or lycopene increased expression of genes involved in lipid metabolism (Fasn, Acaca, Srebf1, Hmgcr, and Ptgs1) (all P < 0.05). The impact of Bco2 genotype was limited to a subset of lycopene-impacted genes (Apc, Mto1, Nfkb1, and Rbm39). Conclusions The TRAMP genotype strongly impacts procarcinogenic gene expression prior to emergence of histopathologic disease. Dietary tomato and lycopene modestly temper these processes, while Bco2 genotype has a limited impact at this early stage. These observed patterns provide insight into the complex interactions between a dietary variable, here tomatoes and lycopene, genes impacting nutrient metabolism, and their modulating influences on oncogene-driven prostate carcinogenesis. These findings provide further mechanistic support, consistent with cancer outcomes in rodents experiments and human epidemiologic studies.

Transcriptomics and Metabolomics Reveal Tomato Consumption Alters Hepatic Xenobiotic Metabolism and Induces Steroidal Alkaloid Metabolite Accumulation in Mice

“…Several mammalian circadian rhythm genes were differentially expressed when comparing red to tangerine tomato supplemented mice (Supporting Table 6 and 10). Tomatoconsuming mice with HCC or early prostate carcinogenesis are susceptible to alterations in circadian rhythm genes including period circadian regulator 2 (Per2), clock circadian regulator (Clock), cryptochrome circadian regulator 2 (Cry2), and aryl hydrocarbon receptor nuclear translocator-like protein 1 (Arntl) [54,55] . However, expression differences did not manifest themselves in healthy, tomato-supplemented animals [55] .…”

“…Tomatoconsuming mice with HCC or early prostate carcinogenesis are susceptible to alterations in circadian rhythm genes including period circadian regulator 2 (Per2), clock circadian regulator (Clock), cryptochrome circadian regulator 2 (Cry2), and aryl hydrocarbon receptor nuclear translocator-like protein 1 (Arntl) [54,55] . However, expression differences did not manifest themselves in healthy, tomato-supplemented animals [55] . Similarly, circadian rhythm gene expression in the current study was not different between tomato-fed versus control animals.…”

Transcriptomics and Metabolomics Reveal Tomato Consumption Alters Hepatic Xenobiotic Metabolism and Induces Steroidal Alkaloid Metabolite Accumulation in Mice

“…Tomato‐consuming mice with HCC or early prostate carcinogenesis are susceptible to alterations in circadian rhythm genes including period circadian regulator 2 ( Per2 ), clock circadian regulator ( Clock ), cryptochrome circadian regulator 2 ( Cry2 ), and aryl hydrocarbon receptor nuclear translocator‐like protein 1 ( Arntl ). [ 59,60 ] However, expression differences did not manifest themselves in healthy, tomato‐supplemented animals. [ 60 ] Similarly, circadian rhythm gene expression in the current study was not different between tomato‐fed versus control animals.…”

“…[ 59,60 ] However, expression differences did not manifest themselves in healthy, tomato‐supplemented animals. [ 60 ] Similarly, circadian rhythm gene expression in the current study was not different between tomato‐fed versus control animals. The implications of differentially expressed circadian rhythm genes when comparing red and tangerine tomato supplemented mice are unclear.…”